Transcript CALCIUM METABOLISM

Corso di Laurea di I livello
Tecnici di Laboratorio Biomedico
Corso integrato Fisiopatologia
Unità didattica: Fisiopatologia endocrina.
La Paratiroide
Parathyroid Gland:
Think Calcium Metabolism =
Stones and Bones
CALCIUM METABOLISM
• PHYSIOLOGY OF CALCIUM
METABOLISM
– ORGAN SYSTEMS INVOLVED
– HORMONES INVOLVED
• HYPERCALCEMIA
• HYPOCALCEMIA
• METABOLIC BONE DISEASES
CALCIUM PHYSIOLOGY:
BLOOD CALCIUM
• BLOOD CALCIUM IS TIGHTLY
REGULATED
– PRINCIPLE ORGAN SYSTEMS
• GUT, BONE, KIDNEYS
– HORMONES
• PARATHYROID HORMONE (PTH), VITAMIN D
– INTEGRATED PHYSIOLOGY OF ORGAN
SYSTEMS AND HORMONES MAINTAIN
BLOOD CALCIUM
CALCIUM PHYSIOLOGY:
BLOOD CALCIUM
• CALCIUM FLUX INTO AND OUT OF BLOOD
– “IN” FACTORS: INTESTINAL ABSORPTION,
BONE RESORPTION
– “OUT” FACTORS: RENAL EXCRETION, BONE
FORMATION (Ca INCORPATION INTO BONE)
– BALANCE BETWEEN “IN” AND “OUT” FACTORS
• ORGAN PHYSIOLOGY OF GUT, BONE, AND
KIDNEY
• HORMONE FUNCTION OF PTH AND
VITMAMIN D
CALCIUM HOMEOSTASIS
DIETARY CALCIUM
THE ONLY “IN”
BONE
DIETARY HABITS,
SUPPLEMENTS
BLOOD CALCIUM
ORGAN PHYS.,
ENDOCRINE
PHYS.
INTESTINAL ABSORPTION
ORGAN PHYSIOLOGY
ENDOCRINE PHYSIOLOGY
KIDNEYS
ORGAN PHYS.
ENDOCRINE PHYS.
URINE
THE PRINCIPLE “OUT”
PARATHYROID HORMONE
(PTH) PHYSIOLOGY
• PTH FUNCTIONS TO PRESERVE NORMAL BLOOD
CALCIUM (AND PHOSPHATE)
– PTH STIMULATES BONE RESORPTION AND,
THUS, INCREASES BLOOD CALCIUM
– PTH STIMULATES RENAL TUBULAR
REABSORPTION OF CALCIUM, AND THUS,
INCREASES BLOOD CALCIUM
– PTH STIMULATES RENAL 1a-HYDROXYLATION
OF 25(OH)VITAMIN D, THUS INDIRECTLY
STIMULATING INTESTINAL ABSORPTION OF
CALCIUM
PTH PHYSIOLOGY
• PTH SECRETION IS INCREASED IN RESPONSE TO
FALLING CALCIUM LEVEL, TO HELP KEEP
CALCIUM NORMAL BY THE ABOVE MECHANISMS
• RISING CALCIUM FEEDS BACK TO THE
PARATHYROIDS TO SUPPRESS PTH SECRETION IN
A CLASSIC ENDOCRINE FEEDBACK LOOP
• THIS LOOP IS MUCH LIKE OTHER ENDOCRINE
FEEDBACK LOOPS YOU’RE FAMILIAR WITH SUCH
AS GLUCOSE AND INSULIN, THYROID HORMONE
AND TSH, ETC.
CALCIUM, PTH, AND VITAMIN D
FEEDBACK LOOPS
BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION
RISING BLOOD Ca
NORMAL BLOOD Ca
FALLING BLOOD Ca
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
STIMULATE PTH
CALCIUM FEEDBACK TO
REGULATE PTH SECRETION
• CALCIUM-SENSING RECEPTOR IN THE PARATHYROIDS
– 7-TRANSMEMBRANE SPANNING PROTEIN RECEPTOR
THAT BINDS CALCIUM EXTRACELLULARLY, AND IS
COUPLED TO SIGNALLING PATHWAYS VIA G-PROTEINS
• THE Ca-SENSING RECEPTOR IS ALSO PRESENT IN THE
KIDNEYS, AND A VARIETY OF OTHER TISSUES
• MECHANISM OF CALCIUM FEEDBACK TO REGULATION OF
PTH SECRETION IS MEDIATED VIA THE Ca-SENSING
RECEPTOR
– INCREASING AMBIENT CALCIUM IS SENSED BY RECEPTOR
AND SUPPRESSES PTH SECRETION
– FALLING AMBIENT CALCIUM IS SENSED BY RECEPTOR AND
STIMULATES PTH SECRETION
CALCIUM SENSING RECEPTOR:
CLINICOPATHOLOGIC CORRELATES
• INACTIVATING MUTATIONS RIGHT-SHIFT THE SETPOINT
FOR PTH SECRETION, SO THAT IT TAKES HIGHER CALCIUM
TO SUPPRESS PTH SECRETION
– IN THE HETEROZYGOUS STATE, IT TAKES HIGHER
AMBIENT CALCIUM TO SUPPRESS PTH SECRETION.
PATIENTS WITH THIS MUTATION HAVE
HYPERCALCEMIA, AND RELATIVELY LOW URINE
CALCIUM LOSSES. THIS IS REFERRED TO AS FAMILIAL
BENIGN HYPOCALCIURIC HYPERCALCEMIA (FBHH). IT IS
A CONDITION FREE OF THE PROBLEMS USUALLY
ASSOCIATED WITH HYPERCALCEMIA.
– IN THE HOMOZYGOUS STATE, IT IS LETHAL IN INFANCY
AS A RESULT OF VERY SEVERE HYPERCALCEMIA.
PTH RECEPTOR
• PTH RECEPTORS ARE TRANSMEMBRANE
PROTEIN RECEPTORS
– FOUND IN A VARIETY OF TISSUES (BONE, KIDNEY, OTHERS).
– PTH RECEPTORS ARE COUPLED TO SECOND MESSENGER
SYSTEMS VIA STIMULATORY G PROEINS (Gs). BINDING PTH TO
THE RECEPTOR CAUSES GDP TO DISSOCIATE FROM Gs AND GTP
TO BIND. THE SIGNAL IS THEN TRANSMITTED TO A VARIETY
OF SECOND MESSENGER SYSTEMS, RESULTING IN
PRODUCTION OF CYCLIC AMP (cAMP), INOSITOL
TRIPHOSPHATE, DIACYLGLYCEROL, AND OTHERS.
– THE PTH RECEPTOR ALSO BINDS THE PARATHYROID
HORMONE RELATED PROTEIN (PTHrP) WITH EQUAL AFFINITY
TO PTH. FOR THIS REASON, THE RECEPTOR IS USUALLY
REFERRED TO AS THE PTH/PTHrP RECEPTOR.
PTH RECEPTOR: CLINICOPATHOLOGIC
CORRELATES
• THERE IS A FAMILY OF DISEASES KNOWN AS
PSEUDOHYPOPARATHYROIDISM.
– CLINICAL MANIFESTATIONS INCLUDE HYPOCALCEMIA THUS
MIMICKING HYPOPARATHYROIDISM. HOWEVER, AFFECTED
INDIVIDUALS ARE RESISTANT TO PTH, NOT DEFICIENT IN PTH. PTH
LEVELS ARE ELEVATED IN THESE PATIENTS.
– THE MOLECULAR DEFECTS IN PSEUDOHYPOPARATHYROIDISM ARE NOT
ALL CHARACTERIZED, ALTHOUGH IN SOME CASES ARE WELL
CHARACTERIZED. A CLASSIC EXAMPLE IS A MUTATION IN ONE OF THE
SUBUNITS OF Gs, SO THAT SIGNAL TRANSDUCTION UPON PTH BINDING
THE RECEPTOR IS NOT TRANSMITTED TO THE SECOND MESSENGER
PATHWAYS
– CONSIDER IN RELATION TO DISEASES OF INSULIN RESISTANCE,
VITAMIN D RESISTANCE, THYROID HORMONE RESISTANCE, ETC.
VITAMIN D PHYSIOLOGY
• VITAMIN D IS A HORMONE BY CLASSIC
CRITERIA: MADE IN ONE PLACE (OR
SEQUENTIALLY SEVERAL PLACES!), AND
ACTING IN OTHER PLACES. THIS
DISTINGUISHES IT FROM OTHER
“CLASSIC” VITAMINS, SUCH AS VITAMIN C,
B VITAMINS, ETC., WHICH ACT AS
COFACTORS IN BIOCHEMICAL
REACTIONS.
VITAMIN D SYNTHESIS
• THE PRECURSOR FOR VITAMIN D
SYNTHESIS IS A STEROL IN THE
CHOLESTEROL BIOSYNTHETIC
PATHWAY, 7-DEHYDROCHOLESTEROL.
– IN THE SKIN, ULTRAVIOLET LIGHT
TRANSFORMS 7-DEHYDROCHOLESTEROL
TO VITAMIN D3
• ROLE OF SUNLIGHT IN VITAMIN D ADEQUACY
VITAMIN D SYNTHESIS
• VITAMIN D3 CIRCULATES TO THE LIVER, WHERE
THE ENZYME 25-HYDROXYLASE HYDROXYLATES
IT TO 25-HYDROXY VITAMIN D (25(OH)VITAMIN D)
– 25-HYDROXYLASE FUNCTIONS
CONSTITUTIVELY WITHOUT INPUT FROM
BLOOD CALCIUM STATUS OR PTH
– 25(OH)VITAMIN D IS THE BEST SCREENING
TEST FOR VITAMIN D ADEQUACY
VITAMIN D SYNSTHESIS
• 25(OH)VITAMIN D CIRCULATES TO THE KIDNEYS,
WHERE THE ENZYME RENAL 1a-HYDROXYLASE
HYDROXYLATES IT TO 1,25(OH)2 VITAMIN D
– THIS IS THE ACTIVE METABOLITE OF VITAMIN
D. 1,25(OH)2 VITAMIN D MEDIATES THE
PHYSIOLOGIC ROLES OF VITAMIN D.
– RENAL 1a-HYDROXYLASE IS REGULATED BY
PTH WHICH STIMULATES ITS ACTIVITY. PTH IS
THE PRINCIPLE PHYSIOLOGIC REGULATOR,
ALTHOUGH CALCIUM CAN AFFECT THE
ACTIVITY.
VITAMIN D SYNTHESIS
SKIN
LIVER
7-DEHYDROCHOLESTEROL
h
VITAMIN D3
VITAMIN D3
KIDNEY
25(OH)VITAMIN D
25-HYDROXYLASE
25(OH)VITAMIN D
1a-HYDROXYLASE
1,25(OH)2 VITAMIN D
(ACTIVE METABOLITE)
TISSUE-SPECIFIC VITAMIN D RESPONSES
VITAMIN D
• THE BODY CAN SUPPLY ITS OWN
VITAMIN D VIA THE SYNTHETIC
PATHWAYS SHOWN ABOVE.
ALTERNATIVELY, VITAMIN D MAY BE
SUPPLIED BY VITAMIN D - ENRICHED
FOODS. THE CLASSIC EXAMPLES
ARE MILK AND MULTIPLE VITAMINS.
VITAMIN D MECHANISM OF ACTION:
VITAMIN D RECEPTOR
• BIOLOGICAL EVOLUTION IS VERY
CONSERVATIVE. VITAMIN D SHARES MANY
SIMILARITIES WITH STEROID HORMONES. IT IS
NOT SURPRISING, THEREFORE, THAT THE
VITAMIN D RECEPTOR SHARES AN
EVOLUTIONARY RELATIONSHIP WITH
RECEPTORS FOR STEROID HORMONES, THYROID
HORMONE, RETINOIDS, AND MANY ORPHAN
RECEPTORS (WITH NO KNOWN LIGAND).
VITAMIN D REPCEPTOR:
TRANSCRIPTIONAL REGULATION
• THE SUPERGENE FAMILY OF NUCLEAR
RECEPTORS THAT INCLUDES THE VITAMIN
D RECEPTOR ALSO INCLUDES RECEPTORS
FOR CORTISOL, ESTROGEN,
TESTOSTERONE, THYROID HORMONE,
ALDOSTERONE, RETINOIC ACID, AND
OTHERS. MANY RECEPTORS IN THIS
FAMILY HAVE NO KNOWN LIGAND, AND
MAY FUNCTION VIA ALTERATIONS IN
PHOSPHORYLATION STATE, AND/OR ??.
VITAMIN D MECHANISM OF
ACTION
VIT D / VDR
RNA POL
5’ UNTRANSLATED REGION
VITAMIN D RESPONSIVE GENE
TRANSCRIPTION START SITE
IN THE NUCLEUS
FUNCTION OF VITAMIN D
•
TISSUE SPECIFICITY
– GUT
• STIMULATE TRANSEPITHELIAL TRANSPORT OF CALCIUM
AND PHOSPHATE IN THE SMALL INTESTINE (PRINCIPALLY
DUODENUM)
– BONE
• STIMULATE TERMINAL DIFFERENTIATION OF
OSTEOCLASTS
• STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS
TO MOBILIZE CALCIUM
– PARATHYROID
• INHIBIT TRANSCRIPTION OF THE PTH GENE (FEEDBACK
REGULATION)
ORGAN PHYSIOLOGY AND
CALCIUM METABOLISM
• THERE ARE THREE PRICIPLE TISSUES
THAT FUNCTION PROMINENTLY IN
CALCIUM HOMEOSTATIS. DISORDERS OF
THESE TISSUES, OR OF THE
CALCIOTROPIC FACTORS THAT AFFECT
THEIR FUNCTION MAY RESULT IN
DISORDERS OF CALCIUM METABOLISM
– INTESTINES
– KIDNEYS
– BONE
GI PHYSIOLOGY
• NORMAL INTESTINAL FUNCTION AND NORMAL
RESPONSE TO VITAMIN D ARE REQUIRED FOR
NORMAL CALCIUM ABSORPTION.
– GI DYSFUNCTION: SHORT BOWEL,
MALABSORPTION SYNDROMES,
INFLAMMATORY BOWEL SYNDROMES
– AVAILABILITY AND FUNCTION OF VITAMIN D
(DIETARY AND/OR ENDOGENOUS)
– DIETARY CALCIUM INTAKE
– DIETARY PHOSPHATE INHIBITS Ca
ABSORPTION
RENAL PHYSIOLOGY
• RENAL FUNCTION
– RESPONSE TO PTH
• 1,25(OH)2D PRODUCTION
• TUBULAR RESPONSE (Ca REABSORPTION)
– NORMAL FUNCTION IN 1,25(OH)2D SYNTHESIS
• 1,25(OH)2D SUPPLEMENTATION IN RENAL
INSUFFICIENCY/FAILURE
– NORMAL TUBULAR PHYSIOLOGY
• GENETIC RENAL CALCIUM LEAK
– HYPERCALCIURIA, WITH SECONDARY
HYPERPARATHYROIDISM
BONE PHYSIOLOGY
• BONE IS A RESERVOIR OF CALCIUM,
CALCIUM EN MASSE BEING REQUIRED TO
MAKE AND MAINTAIN THE SKELETON. TO
BE AN EFFECTIVE RESERVOIR FOR THE
MAINTAINANCE OF NORMAL BLOOD
CALCIUM, CALCIUM MUST BE ABLE TO BE
INCORPORATED INTO, AND LIBERATED
FROM, BONE ON SHORT NOTICE.
BONE PHYSIOLOGY, cont.
• BONE TURNOVER: A COUPLED PROCESS
OF BONE FORMATION AND BONE
RESORPTION (BREAK DOWN)
– TAKES PLACE THROUGHOUT LIFE
– SHIFT TOWARD FORMATION OR
RESORPTION REMOVES Ca FROM
BLOOD OR PUTS Ca INTO BLOOD,
RESPECTIVELY, AND CORRESPONDINGLY AFFECTS BONE MASS.
BONE PHYSIOLOGY, cont.:
BONE TURNOVER
• SKELETAL MASS IN THE HUMAN REACHES
A PEAK AT ABOUT AGE 30
– PRIOR TO THAT, AS SKELETAL MASS IS
INCREASING, BONE FORMATION EXCEEDS
BONE RESORPTION.
– AT PEAK BONE MASS, THE TWO PROCESSES
ARE EXACTLY MATCHED
– AFTER THE AGE OF PEAK BONE MASS,
SKELETAL MASS IS LOST FOR THE REST OF
LIFE
BONE PHYSIOLOGY, cont.
• BONE FORMATION IS MEDIATED BY
OSTEOBLASTS
• BONE RESORPTION IS MEDIATED BY
OSTEOCLASTS
MEASUREMENT OF BONE
TURNOVER
• THE COUPLED PROCESS OF BONE
TURNOVER CAN BE MEASURED BY:
– MARKERS OF OSTEOBLAST METABOLISM
• SERUM BONE-SPECIFIC ALKALINE PHOSPHATASE
• SERUM OSTEOCALCIN
– MARKERS OF OSTEOCLAST METABOLISM
• URINE PRODUCTS OF BONE COLLAGEN
BREAKDOWN
– HYDROXYPROLINE
– N-TELOPEPTIDES
– PYRIDINIUM CROSSLINKS
BONE PHYSIOLOGY, cont.
• HORMONAL CHAIN OF COMMAND:
– NOTE THAT OSTEOCLASTS RESORB BONE, AND THAT
1,25(OH)2D AND PTH STIMULATE BONE RESORPTION.
– HOWEVER, OSTEOCLASTS HAVE RECEPTORS FOR
NEITHER PTH NOR 1,25(OH)2D
– PTH AND 1,25(OH)2D RECEPTORS ARE EXPRESSED ON
OSTEOBLASTS. THE OSTEOBLASTS, IN RESPONSE TO
THESE HORMONES, SEND A PARACRINE SIGNAL TO
OSTEOCLASTS TO TERMINALLY DIFFERENTIATE (VIT. D
INFLUENCE) AND RESORB BONE (PTH INFLUENCE).
BONE PHYSIOLOGY, cont.
• WHEN THE COUPLED PROCESS OF BONE
TURNOVER (FORMATION AND RESORPTION) IS
SHIFTED IN FAVOR OF RESORPTION, THERE IS
RELATIVE OR NET BONE LOSS. THIS OCCURS IN A
VARIETY OF CONDITIONS:
–
–
–
–
–
–
age
menopause in women or hypogonadism in men
glucocorticoid therapy
hyperparathyroidism (primary of secondary)
defects in organ physiology (GI, RENAL, BONE)
others (medications, genes, comorbid conditions, etc.)
BONE PHYSIOLOGY, cont.
• IN A BROAD SENSE, FRACTURE RISK IS
INVERSELY PROPORTIONAL TO BONE MASS
– accelerated bone loss increases fracture risk
• menopause
• chronic and/or high dose glucocorticoid therapy
• others
– failure to reach normal peak bone mass means lower
bone mass per age later in life, and therefore increases
fracture risk
• soda pop doesn’t provide calcium or vitamin D!!
BONE MASS AS A FUNCTION OF
AGE; PERTURBATIONS
PEAK BONE MASS
NORMAL
FAILURE TO REACH PEAK
ACCELERATED LOSS
BONE
MASS
THEORETICAL
FRACTURE
THRESHOLD
AGE
HYPERCALCEMIA
• HYPERCALCEMIA IS THE STATE OF BLOOD
CALCIUM CONCENTRATION ABOVE THE
NORMAL RANGE
• RELATE TO ORGAN PHYSIOLOGY AND
ENDOCRINE PHYSIOLOGY DISCUSSED
ABOVE: “IN” AND “OUT” FACTORS
– GI, RENAL, BONE
– PTH, VITAMIN D
– TO MUCH CALCIUM ENTERING BLOOD AND/OR TOO
LITTLE LEAVING BLOOD
THE STATE OF CIRCULATING
CALCIUM
• CALCIUM CIRCULATES FREE (IONIC) AND
PROTEIN-BOUND
– ROUGHLY 50% FREE (IONIZED), AND 50%
PROTEIN BOUND AND COMPLEXED
– ALBUMIN IS THE PROTEIN RESPONSIBLE FOR
MOST PROTEIN BINDING (~90%)
• IT IS RELATIVELY MEANINGLESS TO
CONSIDER TOTAL CALCIUM CONCENTRATION WITHOUT CONSIDERING ALBUMIN
CONCENTRATION
CIRCULATING CALCIUM, cont.
• IONIZED CALCIUM (FREE CALCIUM)
– RESPONSIBLE FOR CALCIUM FUNCTION
– CAN BE DIRECTLY MEASURED
– GETS AROUND THE CAVEAT REGARDING
SERUM ALBUMIN CONCENTRATION
• ALBUMIN CAN BE SOME DEGREE OF LOW AS A
RESULT OF KIDNEY DISEASE OR LIVER DISEASE.
MEASUREMENT OF IONIZED CALCIUM IN THESE
STATES ACCURATELY REFLECTS CALCIUM
CONCENTRATION.
– THIS IS A RELATIVELY UNDERUTILIZED TEST
HYPERCALCEMIA: SIGNS AND
SYMPTOMS
• SIGNS AND SYMPTOMS DEPEND ON THE
DEGREE OF HYPERCALCEMIA AND
COMORBID CONDITIONS
– THERE IS NO ABSOLUTE VALUE OF BLOOD
CALCIUM AT WHICH SYMPTOMS DEVELOP.
LEVEL OF BLOOD CALCIUM AT WHICH
SYMPTOMS DEVELOP VARY FROM PATIENT TO
PATIENT.
HYPERCALCEMIA: SIGNS AND
SYMPTOMS
• CNS: altered MS, including lethargy, depression,
decreased alertness, confusion, obtundation, and coma
• GI: anorexia, constipation, nausea, and vomiting
• RENAL: diuresis, impaired concentrating ability,
dehydration. Hypercalciuria is a risk for kidney stones.
• SKELETAL: most causes of hypercalcemia are
associated with increased bone resorption, and thus,
fracture risk
• CARDIOVASCULAR: cause/exacerbate HTN,
shortened QT interval
CAUSES OF HYPERCALCEMIA
• HORMONAL
– PRIMARY HYPERPARATHYROIDISM
– HYPERVITAMINOSIS D
– PARANEOPLASTIC (e.g., PTHrP, cytokines)
• NON-HORMONAL
– RENAL FAILURE
– MILK-ALKALI SYNDROME
• DRUGS
– THIAZIDES, LITHIUM, OTHERS
PRIMARY
HYPERPARATHYROIDISM
• 1o HPT is characterized by
–
–
–
–
–
–
hypercalcemia
PTH above the normal range
hypercalciuria
increased risk of fractures
increased risk of kidney stones
seldom causes extreme hypercalcemia unless
confounded by renal failure, dehydration, etc.
PRIMARY
HYPERPARATHYROIDISM
• CAUSES OF 1o HPT
– SPORADIC ADENOMA(S) MOST COMMON CAUSE
– MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN-1):
PARATHYROID TUMORS (AND PITUITARY AND
PANCREAS). LOSS OF ACTIVITY OF TUMOR SUPPRESSOR
GENE (the MENIN gene) FOUND ON HUMAN
CHROMOSOME 11. THIS IS RARE.
– MEN-2a: PARATHYROID TUMORS, MEDULLARY THYROID
CANCER (OR HYPERPLASIA), AND
PHEOCHROMOCYTOMA. ACTIVATING MUTATION OF ret
PROTO-ONCOGENE ON HUMAN CHROMOSOME 10. THIS
IS RARE.
PRIMARY
HYPERPARATHYROIDISM
• CAUSES OF 1o HPT, cont.
– FAMILIAL HYPERPARATHYROIDISM: 1o HPT WITHOUT
THE OTHER TUMORS SEEN IN MEN-1 OR MEN-2a. THE
GENE IS NOT KNOWN, BUT MAPS TO A REGION ON
HUMAN CHROMOSOME 1.
– FAMILIAL BENIGN HYPOCALCIURIC HYPERCALCEMIA:
AN INACTIVATING MUTATION IN THE CALCIUM SENSING
RECEPTOR FOUND IN THE PARATHYROIDS AND
KIDNEYS, AND RESULTS IN HYPERCALCEMIA AND
HYPERPARATHYROIDISM, BUT WITH LOW URINARY
CALCIUM.
HYPERVITAMINOSIS D
• EXCESSIVE INTAKE OF VITAMIN D
– RELATIVELY HARD TO DO IF ALL RELEVANT ORGAN
SYSTEMS ARE FUNCTIONING PROPERLY; GENERALLY
REQUIRES PRESCRIPTION STRENGTH VITAMIN D,
PARTICULARLY 1,25(OH)2D (CALCITRIOL)
• EXCESSIVE PRODUCTION OF 1,25(OH)2D
– EXTRA-RENAL 1-HYDROXYLATION OF 25(OH)VITAMIN D
BY AN ENZYME WITH 1-HYDROXYLASE ACTIVITY, BUT
WHICH IS DISTINCT FROM THE RENAL ENZYME
• USUALLY ASSOCIATED WITH GRANULOMAS
(MACROPHAGES) OR ABNORMAL LYMPHOID TISSUE (B
CELL LYMPHOMA)
• NOT REGULATED BY PTH OR CALCIUM
HYPERVITAMINOSIS D:
CLINICAL CHARACTERISTICS
•
•
•
•
HYPERCALCEMIA
SUPPRESSED PTH
INCREASED 1,25(OH)2D
SOURCE
– DIET?
– GRANULOMA?
• SARCOIDOSIS MOST COMMON; ALSO TB, OTHERS
– LYMPHOMA?
PARANEOPLASTIC
HYPERCALCEMIA
• HYPERCALCEMIA MAY BE SEEN WITH A NUMBER OF
CANCERS
– LUNG MOST COMMON, BUT ALSO SEEN WITH BREAST, RENAL,
LYMPHOMAS, OTHERS
• CERTAIN CANCERS MAY PRODUCE A HORMONE-LIKE
FACTOR THAT ACTS IN AN ENDOCRINE FASHION, OR A
FACTOR THAT ACTS IN A PARACRINE FASHION, TO CAUSE
HYPERCALCEMIA, PRIMARILY BY BONE RESORPTION
• HYPERCALCEMIA CAUSED BY A “HORMONE” FROM A
CANCER IS OFTEN REFERRED TO AS THE HUMORAL
HYPERCALCEMIA OF MALIGNANCY
• PARANEOPLASTIC HYPERCALCEMIA IS MOST COMMON IN
A SICK HOSPITALIZED PATIENT
PARANEOPLASTIC
HYPERCALCEMIA: PTHrP
• PARATHYROID HORMONE RELATED PROTEIN
(PTHrP) IS THE BEST CHARACTERIZED TUMOR
PRODUCT THAT IS ASSOCIATED WITH THE
HUMORAL HYPERCALCEMIA OF MALIGNANCY
– SHARES N-TERMINAL SEQUENCE HOMOLOGY WITH PTH
• THUS THE NAME PTHrP
– BINDS TO PTH RECEPTORS
• THIS RECEPTOR IS USUALLY REFERRED TO AS THE
PTH/PTHrP RECEPTOR FOR THIS REASON
• MEDIATES BONE RESORPTION, RENAL Ca REABSORPTION
• ASSOCIATED WITH RELATIVELY SEVERE HYPERCALCEMIA
PTHrP, cont.
• PTHrP
– EXPRESSION IN NOT REGULATED BY CALCIUM OR
1,25(OH)2D
• UNREGULATED, CONSTITUTIVE EXPRESSION
– NOTE THAT 1o HPT IS A SHIFT IN “SET POINT” FOR PTH
SECRETION. THE SECRETION OF PTHrP IS NOT A “SET POINT”
ISSUE. THIS ACCOUNTS FOR THE FACT THAT PTHrP OFTEN
CAUSES A MORE SEVERE HYPERCALCEMIA THAN 1o HPT.
– MEASUREMENT AVAILABLE IN THE CLINICAL LAB
– BIOCHEMICAL PROFILE:
•
•
•
•
HYPERCALCEMIA (often severe)
SUPPRESSED PTH
PTHrP ELEVATED (ASSAY CAVEATS)
1,25(OH)2D USUALLY NORMAL (NOT AS HIGH AS IN 1o HPT)
PTHrP INTERACTIONS
TUMOR
BONE: resorption
PTHrP
KIDNEY: tubular
reabsorption
HYPERCALCEMIA
PARATHYROIDS:
suppress PTH secretion
NOTE: NO
FEEDBACK
LOOPS TO
TUMOR
MULTIPLE MYELOMA
• ONE OF THE FIRST CANCERS RECOGNIZED TO
CAUSE HYPERCALCEMIA
– THE FACTOR IS NOT WELL CHARACTERIZED, AND
APPEARS TO BE MEDIATED BY A FAMILY OF CYTOKINES
(PREVIOUSLY REFERRED TO AS OSTEOCLAST ACTIVATING
FACTOR’S or OAF’s)
– BIOCHEMICAL PROFILE
•
•
•
•
HYPERCALCEMIA
SUPPRESSED PTH
NORMAL PTHrP
NORMAL OR LOW 1,25(OH)2D
NON-HORMONAL
HYPERCALCEMIA
• MILK-ALKALI SYNDROME:
– INTAKE OF HIGH DOSES OF CALCIUM AND
ABSORBABLE ANTACID (SUCH AS NaCO3)
– RARE CAUSE OF HYPERCALCEMIA NOW
• MORE COMMONLY DESCRIBED IN EARLIER PART OF
20TH CENTURY (NO H2 BLOCKERS OR PPI’S!!)
– MECHANISM NOT ABSOLUTELY CLEAR:
• INCREASED INTESTINAL ABSORPTION
• DECREASED RENAL CLEARANCE
– PTH SUPPRESSED, PTHrP NORMAL, 1,25(OH)2D
NORMAL
RENAL FAILURE-ASSOCIATED
HYPERCALCEMIA
• RENAL FAILURE MAY CAUSE EITHER HYPERCALCEMIA OR
HYPOCALCEMIA
• HYPERCALCEMIA USUALLY RESULTS FROM A
COMBINATION OF FACTORS INCLUDING DECREASED
CALCIUM CLEARANCE AND INCREASED BONE
RESORPTION, +/- GI UPTAKE
– PTH ELEVATION
– LOW ENDOGENOUS 1,25(OH)2D
• EXOGENOUS 1,25(OH)2D MAY CONTRIBUTE TO
HYPERCALCEMIA
– CALCIUM AND PHOSPHATE RENAL CLEARANCE IS ABOLISHED,
AND DIALYSIS DOES A RELATIVELY POOR JOB AT CLEARANCE
(COMPARED TO, SAY, POTASSIUM)
DRUG-INDUCED
HYPERCALCEMIA
• THIAZIDE DIURETIC-INDUCED
HYPERCALCEMIA:
– STIMULATE RENAL TUBULAR CALCIUM
REABSORPTION
• DECREASE URINARY LOSS OF CALCIUM
– UNCOMMON CAUSE OF HYPERCALCEMIA AT
DOSES USED TO TREAT HYPERTENSION
• MORE LIKELY IN COMBINATION WITH RENAL
DISEASE, 1o HPT, ETC.
DRUG-INDUCED
HYPERCALCEMIA, cont.
• LITHIUM-INDUCED HYPERCALCEMIA:
– LITHIUM MAY BE ASSOCIATED WITH
HYPERCALCEMIA AT DOSES ROUTINELY USED
TO TREAT BIPOLAR AFFECTIVE DISORDER
(DURATION OF THERAPY IS A FACTOR)
– SHIFTS “SET POINT” FOR CALCIUM
REGULATION OF PTH SECRETION
• PATHOPHYSIOLOGIC CORRELATE: CALCIUMSENSING RECEPTOR, ABOVE
– AUGMENTS PTH EFFECT AT TARGET TISSUES
(BONE AND KIDNEY)
DRUG-INDUCED
HYPERCALCEMIA, cont.
• HIGH DOSES OF VITAMIN A, OR RETINOIC
ACID-INDUCED HYPERCALCEMIA:
– VARIOUS RETINOIDS ARE USED IN TREATMENT OF
ACNE, AND CERTAIN HEMATOLOGIC MALIGNANCIES
– BIND TO RECEPTORS IN THE SUPERGENE FAMILY OF
NUCLEAR RECEPTORS WHICH INCLUDES STEROID
HORMONE, THYROID, VITAMIN D RECEPTORS, ETC.
– APPEAR TO DIRECTLY ACTIVATE OSTEOCLASTS AND
MEDIATE BONE RESORPTION
– HYPERCALCEMIA IS ASSOCIATED WITH SUPPRESSED
PTH, NORMAL PTHrP, NORMAL 1,25(OH)2D
HYPOCALCEMIA
• THE STATE OF BLOOD CALCIUM
BELOW THE NORMAL RANGE
– MOST ACCURATELY ASSESSED WITH
IONIZED CALCIUM
– TOTAL CALCIUM CANNOT BE
ACCURATELY INTERPRETED WITHOUT
KNOWING SERUM ALBUMIN
– FAIRLY UNCOMMON
HYPOCALCEMIA: SIGNS AND
SYMPTOMS
• AS WAS NOTED ABOVE FOR
HYPERCALCEMIA, THERE IS NO
FIXED LEVEL OF BLOOD CALCIUM AT
WHICH SIGNS AND/OR SYMPTOMS
DEVELOP. THIS VARIES FROM
PATIENT TO PATIENT, AND MAY BE
INFLUENCED BY COMORBID
CONDITIONS.
HYPOCALCEMIA: SIGNS AND
SYMPTOMS
• NEUROMUSCULAR:
INVOLUNTARY MUSCLE
CONTRACTION (TETANY), 7TH CRANIAL NERVE
EXCITABILITY (CHVOSTEK’S SIGN), NUMBNESS AND
TINGLING IN FACE, HANDS, AND FEET, TROUSSEAU’S SIGN
• CNS: IRRITABILITY, SEIZURES, PERSONALITY CHANGE,
IMPAIRED COGNITION
• CARDIOVASCULAR: QT PROLONGATION ON ECG, IN
THE EXTREME, ELECTROMECHANICAL DISSOCIATION MAY
OCCUR
CAUSES OF HYPOCALCEMIA
• HYPOPARATHYROIDISM
–
–
–
–
POSTSURGICAL (MOST COMMON)
AUTOIMMUNE
PSEUDOHYPOPARATHYROIDISM (PTH RESISTANCE)
IDIOPATHIC
• HYPOVITAMINOSIS D
– DIETARY DEFICIENCY
– RICKETS (RACHITISMO), OSTEOMALACIA
• ORGAN DYSFUNCTION
– GI MALABSORPTION, RENAL LOSS
• ENDOCRINE RESPONSE TO NONHYPOPARATHYROID HYPOCALCEMIA
– SECONDARY HYPERPARATHYROIDISM (2o HPT)
HYPOCALCEMIA:
HYPOPARATHYROIDISM
• POSTSURGICAL
– MOST COMMON CAUSE OF HYPOPARATHYROIDISM
– VITAL IMPORTANCE OF EXCELLENT SURGEON
EXPERIENCED IN THYROID AND PARATHYROID
SURGERY
• AUTOIMMUNE
– MAY CLUSTER WITH OTHER AUTOIMMUNE ENDOCRINE
DISEASES, INCLUDING IDDM, AUTOIMMUNE THYROID
DISEASE, ADDISON’S, ETC. THIS IS RATHER
UNCOMMON.
HYPOCALCEMIA:
HYPOVITAMINOSIS D
• THIS CATEGORY INCLUDES A
NUMBER OF CONDITIONS RELATED
TO VITAMIN D AVAILABILITY,
METABOLISM, OR FUNCTION
–
–
–
–
INADEQUATE DIETARY SUPPLY
INADEQUATE EXPOSURE TO SUNLIGHT
DEFECTS IN VITAMIN D SYNTHESIS
DEFECTS IN VITAMIN D RECEPTOR
DEFECTIVE VITAMIN D
FUNCTION
• CLINICAL SYNDROMES BROADLY
CATEGORIZED AS RICKETS (rachitismo)
AND OSTEOMALACIA.
• DIMINISHED GI ABSORPTION OF Ca
• TENDENCY TOWARD
HYPOCALCEMIA
– SECONDARY HYPERPARATHYROIDISM
NON-PARATHYROID HYPOCALCEMIA:
SECONDARY HYPERPARATHYROIDISM
• IN HYPOVITAMINOSIS D (RICKETS AND
OSTEOMALACIA), LOW LEVELS OF, OR
DEFECTIVE FUNCTION OF, VITAMIN D CAUSE
TENDENCY TOWARD HYPOCALCEMIA. THE
PARATHYROIDS RESPOND APPROPRIATELY BY
INCREASING PTH SECRETION TO MAINTAIN
NORMAL BLOOD CALCIUM.
• THIS IS REFERRED TO AS SECONDARY
HYPERPARATHYROIDISM: ELEVATED PTH IN
RESPONSE TO (SECONDARY TO) SOME NONPARATHYROID PROBLEM
SECONDARY
HYPERPARATHYROIDISM
• CAUSES: UNLIKE 1o HPT, WHICH IS A PRIMARY
DYSFUNCTION OF PARATHYROID TISSUE, 2o HPT IS
A NORMAL PHYSIOLOGIC RESPONSE OF THE
PARATHYROIDS TO A THREAT OF HYPOCALCEMIA
• THREE MAIN CATEGORIES OF NON-PARATHYROID
DYSFUCTION
– PROBLEMS WITH INTESTINAL ABSORPTION OF CALCIUM
– INAPPROPRIATE URINARY LOSSES OF CALCIUM (RENAL
LEAK)
– DISORDERS OF VITAMIN D (DEFICIENCY, METABOLIC
ERRORS, RESISTANCE, ETC.)
RICKETS AND
OSTEOMALACIA
• DISEASES OF DEFECTIVE BONE MINERALIZATION
• THESE DISEASES ARE PATHOPHYSIOLOGICALLY RELATED,
AND DIFFER MAINLY IN THE AGE AT WHICH THEY BECOME
MANIFEST
– RICKETS IS A DISEASE OF CHILDHOOD
– OSTEOMALACIA IS A DISEASE OF ADULTHOOD
• WIDE RANGING CATEGORY OF DISEASE
–
–
–
–
DISORDERS OF VITAMIN D
PHOSPHATE DEFICIENCY
CHRONIC RENAL FAILURE (ALSO RENAL OSTEODYSTROPHY)
PRIMARY DISORDERS OF BONE METABOLISM
RICKETS AND OSTEOMALACIA:
CLINICAL MANIFESTATIONS
• RICKETS MAY RESULT IN CHARACTERISTIC BONY
DEFORMITIES IN CHILDREN
– OSTEOMALACIA IN ADULTS GENERALLY DOES NOT
CAUSE BONY DEFORMITIES
• RICKETS USUALLY IS ASSOCIATED WITH SHORT
STATURE
– OSTEOMALACIA (ONSET IN ADULTHOOD) DOES NOT
CAUSE SHORT STATURE
• PATIENTS MAY SUFFER BONE PAIN (NOT SEEN IN
OSTEOPOROSIS UNLESS THERE IS A FRACTURE)
• FRACTURE RISK IS INCREASED
RICKETS AND
OSTEOMALACIA: CAUSES
• NUTRITIONAL DEFICIENCY OF VITAMIN D AND/OR
INADEQUATE SUNLIGHT EXPOSURE:
– EASILY TREATED WITH DIETARY SUPPLEMENTATION
• FORTIFIED MILK - PROVIDES VITAMIN D AND CALCIUM
• MULTIPLE VITAMIN - PROVIDES VITAMIN D ONLY
• EITHER WAY, MUST ASSURE ADEQUATE CALCIUM WITH THE
VITAMIN D
• DEFECTIVE RENAL 1a-HYDROXYLATION OF 25(OH) VIT. D
– AUTOSOMAL RECESSIVE
– CHARACTERIZED BY HYPOCALCEMIA, HYPOPHOSPHATEMIA,
SECONDARY HYPERPARATHYROIDISM, LOW 1,25(OH)2D, AND
INCREASED ALKALINE PHOSPHATASE
– TREATMENT IS BY GIVING 1,25(OH)2D AND CALCIUM
RICKETS AND OSTEOMALACIA:
CAUSES, cont.
• TISSUE RESISTANCE TO 1,25(OH)2D
– AUTOSOMAL RECESSIVE, OR ACQUIRED
– DEFECT IN NUCLEAR RECEPTOR FOR VITAMIN D
• DEFECTIVE SYNTHESIS OF RECEPTOR
• DEFECTIVE AFFINITY OF RECEPTOR FOR 1,25(OH)2D
• DEFECTIVE ABILITY OF 1,25(OH)2D/VITAMIN D RECEPTOR
COMPLEX TO INTERACT WITH DNA OR ACTIVATE
TRANSCRIPTIONAL MACHINERY PROPERLY
– TREATMENT IS WITH 1,25(OH)2D AND CALCIUM
• RESPONSE TO THERAPY IS VARIABLE GIVEN DIVERSITY OF
MOLECULAR DEFECTS (ABOVE)
RICKETS AND OSTEOMALACIA:
CAUSES, cont.
• ANITCONVULSANT-INDUCED OSTEOMALACIA:
– PATIENTS TREATED CHRONICALLY WITH
DIPHENYLHYDANTOIN (PHENYTOIN, DILANTIN©) OR
PHENOBARBITAL FOR SEIZURE DISORDERS ARE AT RISK
FOR ANTICONVULSANT-INDUCED OSTEOMALACIA
– THESE DRUGS ALTER AND ACCELERATE HEPATIC
METABOLISM OF VITAMIN D, AND THIS IS THOUGHT TO
PLAY A MAJOR ROLE IN THIS DISORDER
– ASSURANCE OF ADEQUATE VITAMIN D INTAKE IS
ENCOURAGED IN THESE PATIENTS
– NEWER ANTICONVULSANTS, SUCH AS VALPROIC ACID,
CARBAMAZEPINE, GABAPENTIN, ETC. HAVE NOT BEEN
IMPLICATED AS OF YET